The present invention is generally in the area of polymeric drug delivery devices.
Controlled release systems for drug delivery are often designed to administer drugs in specific areas of the body. In the case of drug delivery via the gastrointestinal tract, it is critical that the drug not be entrained beyond the desired site of action and eliminated before it has had a chance to exert a topical effect or to pass into the bloodstream. If a drug delivery system can be made to adhere to the lining of the appropriate viscus, its contents will be delivered to the targeted tissue as a function of proximity and duration of the contact.
An orally ingested product can adhere to either the epithelial surface or the mucus. For the delivery of bioactive substances, it can be advantageous to have a polymeric drug delivery device adhere to the epithelium or to the mucous layer. Bioadhesion in the gastrointestinal tract proceeds in two stages: (1) viscoelastic deformation at the point of contact of the synthetic material into the mucus substrate, and (2) formation of bonds between the adhesive synthetic material and the mucus or the epithelial cells. In general, adhesion of polymers to tissues may be achieved by (i) physical or mechanical bonds, (ii) primary or covalent chemical bonds, and/or (iii) secondary chemical bonds (i.e., ionic). Physical or mechanical bonds can result from deposition and inclusion of the adhesive material in the crevices of the mucus or the folds of the mucosa. Secondary chemical bonds, contributing to bioadhesive properties, consist of dispersive interactions (i.e., Van der Waals interactions) and stronger specific interactions, which include hydrogen bonds. The hydrophilic functional groups primarily responsible for forming hydrogen bonds are the hydroxyl and the carboxylic groups.
Several microsphere formulations have been proposed as a means for oral drug delivery. These formulations generally serve to protect the encapsulated compound and to deliver the compound into the blood stream. Enteric coated formulations have been widely used for many years to protect drugs administered orally, as well as to delay release. Other formulations designed to deliver compounds into the blood stream, as well as to protect the encapsulated drug, are formed of a hydrophobic protein, such as zein, as described in PCT/U.S. Pat. No. 90/06430 and PCT/U.S. Pat. No. 90/06433; "proteinoids", as described in U.S. Pat. No. 4,976,968 to Steiner; or synthetic polymers, as described in European Patent application 0 333 523 by The UAB Research Foundation and Southern Research Institute. EPA 0 333 523 describes microparticles of less than ten microns in diameter that contain antigens, for use in oral administration of vaccines. The microparticles are formed of polymers such as poly(lactide-co-glycolide), poly(glycolide), polyorthoesters, poly(esteramides), polyhydroxybutyric acid and polyanhydrides, and are absorbed through the Peyer's Patches in the intestine, principally as a function of size.
Duchene et al., Drug Dev. Ind. Pharm., 14, 283-318 (1988) is a review of the pharmaceutical and medical aspects of bioadhesive systems for drug delivery. Polycarbophils and acrylic acid polymers were noted as having the best adhesive properties. "Bioadhesion" is defined as the ability of a material to adhere to a biological tissue for an extended period of time. Bioadhesion is clearly one solution to the problem of inadequate residence time resulting from the stomach emptying and intestinal peristalsis, and from displacement by ciliary movement. For sufficient bioadhesion to occur, an intimate contact must exist between the bioadhesive and the receptor tissue, the bioadhesive must penetrate into the crevice of the tissue surface and/or mucus, and mechanical, electrostatic, or chemical bonds must form. Bioadhesive properties of polymers are affected by both the nature of the polymer and by the nature of the surrounding media.
Others have explored the use of bioadhesive polymers. PCT WO 93/21906, the disclosure of which is incorporated herein by reference, discloses methods for fabricating bioadhesive microspheres and for measuring bioadhesive forces between microspheres and selected segments of the gastrointestinal tract in vitro. Smart et al., J. Pharm. Pharmacol., 36:295-299 (1984), reported a method to test adhesion to mucosa using a polymer coated glass plate contacting a dish of mucosa. A variety of polymeric materials were tested, including sodium alginate, sodium carboxymethyl-cellulose, gelatin, pectin and polyvinylpyrrolidone. Gurney et al., Biomaterials, 5:336-340 (1984) reported that adhesion may be effected by physical or mechanical bonds; secondary chemical bonds; and/or primary, ionic or covalent bonds. Park et al., "Alternative Approaches to Oral Controlled Drug Delivery: Bioadhesives and In-Situ Systems," in J. M. Anderson and S. W. Kim, Eds., "Recent Advances in Drug Delivery," Plenum Press, New York, 1984, pp. 163-183, reported a study of the use of fluorescent probes in cells to determine adhesiveness of polymers to mucin/epithelial surface, which indicated that anionic polymers with high charge density appear to be preferred as adhesive polymers.
Mikos et al., in J. Colloid Interface Sci., 143:366-373 (1991) and Lehr et al., J. Controlled Rel. Soc., 13:51-62 (1990) reported a study of the bioadhesive properties of polyanhydrides and polyacrylic acid, respectively, in drug delivery. Lehr et al. screened microparticles formed of copolymers of acrylic acid using an in vitro system and determined that the copolymer "Polycarbophil" has increased adhesion.
In general, gastrointestinal (GI) mucus is made of 95% water and 5% electrolytes, lipids, proteins and glycoproteins, as described by Spiro, R. G., Annual Review of Biochemistry, 39:599-638 (1970); and Labat-Robert, J. and Decaeus, C., Pathologie et Biologie (Paris), 24:241 (1979). However, the composition of the latter fraction can vary greatly. Proteins, including the protein core of the glycoproteins, can made up anywhere from 60 to 80% of this fraction. Horowitz, M. I., "Mucopolysaccharides and Glycoproteins of the Alimentary Tract" in Alimentary Canal (Eds. C. F. Code), pp. 1063-1085 (Washington: American Physiological Society, 1967). The glycoproteins typically have a molecular weight of approximately two million and consist of a protein core (approximately 18.6-25.6% by weight) with covalently attached carbohydrate side chains (approximately 81.4-74.4% by weight) terminating in either L-fucose or sialic acid residues. Spiro, R. G., Annual Review of Biochemistry, 39:599-638 (1970); Scawen, M. & Allen, A., "The Action of Proteolytic Enzymes on the Glycoprotein from Pig Gastric Mucus," Biochemical Journal, 163:363-368 (1977); Horowitz, M. I. and Pigman, W., The Glycoconjugates, pp. 560 (New York: Academic Press, Inc., 1977); and Pigman, W. & Gottschalk, A., "Submaxillary Gland Glycoproteins" in Glycoproteins: Their Composition, Structure and Function (eds. A. Gottschalk), pp. 434-445 (Amsterdam: Elsevier Publishing Company, Inc., 1966). Species and location differences in the composition of these glycoproteins have been reported by Horowitz, M. I., "Mucopolysaccharides and Glycoproteins of the Alimentary Tract" in Alimentary Canal (eds. C. F. Code), pp. 1063-1085 (Washington: American Physiological Society, 1967).
It has been shown that the gastric mucous layer thickness typically varies from 5 to 200 .mu. in the rat and 10 to 400 .mu. in man. Occasionally, however, it can reach thicknesses as great as 1000 .mu. in man, as described by Spiro, R. G., "Glycoproteins," Annual Review of Biochemistry, 39:599-638 (1970); Labat-Robert, J. and Decaeus, C., Pathologie et Biologie (Paris) 24:241 (1979); and Allen et al., "Mucus Glycoprotein Structure, Gel Formation and Gastrointestinal Mucus Function" in J. Nugent & M. O'Connor, Eds., Mucus and Mucosa, Ciba Foundation Symposium 109, Pitman, London, 1984, pp. 137.
There is a need for methods for controlling or increasing the absorption of pharmaceutical agents from polymeric drug delivery devices such as polymeric microspheres through mucosal membranes. There also is a need for methods for delaying transit of the devices through nasal or gastrointestinal passages. It is therefore an object of the present invention to provide methods for improving the bioadhesive properties of polymeric drug delivery devices such as microspheres, tablets, capsules and stents. It is another object of the invention to provide methods for improving the adhesion of drug delivery devices such as microspheres to mucosal membranes including buccal and nasal membranes and membranes of the gastrointestinal and reproductive tracts. It is a further object of the invention to provide polymeric drug delivery devices with improved ability to bind to mucosal membranes which can be used to deliver a wide range of drugs or diagnostic agents in a wide variety of therapeutic applications.